Antibodies that specifically hind tumor surface antigens are used to deliver cytotoxic drugs in the form of antibody drug conjugates (ADCs). Cytotoxic drugs are typically conjugated to antibodies at cysteine or lysine residues. The number of molecules of a drug conjugated per antibody, also termed the drug-to-antibody ratio (“DAR”), is typically a distribution of species ranging from 0-8. The DAR for a manufacturing batch of ADC is determined empirically using spectrophotometric measurements and ADC therapeutic compositions typically contain a mixture of ADC species that differ in drug load. Thus, the DAR for an ADC batch represents the average DAR of the ADC species within the hatch.
ADC cancer therapeutics and antibody cancer therapeutics are both formulated based on nominal antibody protein concentration and must conform to specification. While the drug product label gives information about the “nominal” or target protein concentration, the drug concentration in the vial may vary relative to the target antibody concentration because of the allowed variation in DAR, even while conforming to the acceptance criteria. The potency of ADCs is generally linear relative to concentration. Unlike antibodies, ADCs have an additional potential for variable potency due to the DAR. A typical specification for antibody concentration and DAR allows the concentration of cytotoxic drug in the ADC product vial to vary somewhat from batch-to-batch when patient dosing is based on nominal antibody concentration.
It is important that patients receive an ADC dose that is both safe and effective. Improved methods of formulating ADC compositions would advantageously reduce variability in potency, efficacy, and/or toxicity between batches and ensure that patients receive an ADC within the intended therapeutic range.